Dietary supplement composition for blood lipid health

ABSTRACT

A method for enhancing gastrointestinal motility in humans and other mammals comprises administering a therapeutically effective amount of a composition having one or more long chain (C24-C36) primary alcohols as policosanols dispersed in one or more food-grade fats or oils, wherein the particle sizes of the alcohols are substantially less than 10 microns.

RELATED APPLICATION

This application is a continuation-in-part application based upon priorfiled utility application Ser. No. 11/671,757 filed Feb. 6, 2007, whichis based upon provisional application Ser. No. 60/771,003 filed Feb. 7,2006, the disclosures of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to dietary supplements, and, moreparticularly to the formulation of such supplements containing fattyalcohols.

BACKGROUND OF THE INVENTION

Cholesterol is an essential component in the body and used in cellmembranes. Excessive levels, however, can lead to hypercholesterolemiaand atherosclerosis, which can result in coronary heart disease.Cholesterol is transported via: high-, low-, intermediate-, and verylow-density lipoproteins; chylomicron remnants; and chylomicrons. Highlevels of high-density lipoproteins are desirable because they transportcholesterol from the peripheral tissues to the liver, therebymaintaining cholesterol homeostasis. The main transport mechanism,however, is low-density lipoprotein, which moves cholesterol in theblood plasma and incorporates it into cell membranes. Increased levelsof low-density lipoprotein, however, can interfere with uptake bindingmechanisms.

Statin drugs such as atorvastatin, fluvastatin, pravastatin andsimvastatin are often administered to those suffering from cholesterolissues. These drugs inhibit competitively 3-hydroxy-3-methylglutarylcoenzyme A reductase, thereby reducing cholesterol synthesis. Sideeffects of statins can include myositis, headache, rash, angioedema,gastrointestinal effects and altered liver functions. In addition, thesedrugs should not be used in patients with renal failure or in peoplewith compromised liver function (Taylor et al. 2003).

Dietary fatty acid intake can influence many health factors, but muchinterest has been placed on the n-3 (omega-3) fatty acids. Theseessential fatty acids include α-linolenic (ALA), eicosapentaenoic (EPA)and docosahexaenoic acid (DHA). Various studies have shown that n-3fatty acids are essential for normal growth and development. They mayalso play a critical role in the prevention and treatment of coronaryheart disease, hypertension, diabetes and other inflammatory andautoimmune disorders (Simopoulos 1999). ALA is present in certainvegetable oils (flaxseed, cranberry seed, canola and chia) whereas EPAand DHA are found in fish, fish oil and algae products.

Between ethnic dietary groups it has been shown that the higher ratio ofn-6 to n-3 in thrombocyte phospholipids can be a cause for a higherdeath rate from cardiovascular disease. This increased ratio alsoresults in increased rates of type 2 diabetes, of which atherosclerosisis a major complication (Weber, 1991). Achieving target levels of n-3fatty acids can be difficult with modern western diets deficient in ALA,EPA and DHA, and excessive in the n-6 linoleic acid. Target tissueconcentrations for ALA and EPA can be met with consumption of ALA(Mantzioris et al. 2000). A primary cardiovascular benefit from n-3fatty acid ingestion can be reduced blood clotting in vessel walls andreduced ventricular arrhythmias, (Zhao et al. (2004)). Some studies havefound a dose-response relation between n-3 intake and beneficial effectson cardiovascular disease risk factors. Some studies have shown aninverse relationship between ALA intake and risk of sudden cardiac death(Albert et al. (2005)).

Policosanols can be defined as a mixture of long chain (C24-C36)aliphatic primary alcohols, which are commonly derived from sugar cane,rice bran, beeswax, wheat or sorghum. Predominant alcohols in this groupare tetracosanol, hexacosanol, octacosanol and triacontanol.

Policosanols can lower cholesterol levels by inhibiting cholesterolbiosynthesis via downregulation of 3-hydroxy-3-methylglutaryl Coenzyme Aenzyme expression (Menendez et al. 1994, McCarty 2002). A study byHernandez et al. (1992) found a reduction in serum cholesterol levels ofsubjects taking 20 mg policosanol per day for 4 weeks. Significantdecreases in LDL levels, with increased levels of HDL were also noticed.Another double-blind randomized study by Castano, et al. (1999)investigated the effects of policosanol and pravastatin on the lipidprofile in older hypercholesterolemic patients. Policosanol was found toincrease HDL levels, but was also more effective than pravastatin inlowering LDL levels and the LDL:HDL ratio.

Policosanols can also protect lipoproteins from peroxidation, in bothlipid and protein moieties (Menendez et al. 1999). This can be animportant effect, since LDL oxidation is thought to be a necessary stepin the development of atherosclerosis.

Policocanols may provide fewer side effects than statins, increase HDLcholesterol levels and have a reduced cost (Taylor et al. 2003).

One issue with policosanols are poor solubility, and difficulty withabsorption in the gut. Human studies with [³H]-octacosanol showed themajority (81-91%) of total radioactivity was excredited in the feces,and only 1.2% of total radioactivity was found in urine (Mas, 2000).

Reducing parent the particle size of poorly solube compounds such aspolicosanol to a micron or sub-micron range, improved absorption andbioavailability is desirable.

Copending parent application Ser. No. 11/671,757 filed Feb. 7, 2006,discloses a human or animal dietary supplement composition thatcomprises a blood lipid health-effective amount of one or more longchain (C24-C36) primary alcohols (policosanols) dispersed in one or morefood-grade fats or oils, wherein the particle sizes of the alcohols aresubstantially less than 10 microns.

SUMMARY OF THE INVENTION

During trials, it was found that positive and advantageous resultsfurther included reductions in base level for AST and ALT and anincrease in the AST/ALT ratio. Also, there was a reduction ingastrointestinal esophageal reflux disease (GERD) symptoms and areduction of irritable bowel syndrome symptoms.

In accordance with a non-limiting aspect, the method enhancesgastrointestinal motility in humans and other mammals. The methodcomprises administering a therapeutically effective amount of acomposition having one or more long chain (C24-C36) primary alcohols aspolicosanols dispersed in one or more food-grade fats or oils, whereinthe particle sizes of the alcohols are substantially less than 10microns.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Different embodiments will now be described more fully hereinafter withreference to the accompanying drawings, in which preferred embodimentsare shown. Many different forms can be set forth and describedembodiments should not be construed as limited to the embodiments setforth herein. Rather, these embodiments are provided so that thisdisclosure will be thorough and complete, and will fully convey thescope to those skilled in the art.

The natural dietary supplement industry represents a $300 billion dollarmarketplace worldwide. Many natural botanical materials and extractshave been used by mankind for health purposes for thousands of years. Insome parts of the world, natural health products are preferred overchemical or pharmaceutical ones due to reasons of religion, culture,safety, cost and demonstrated efficacy.

Among the botanical products that have a history of use in support ofhuman blood lipid health are certain fatty alcohols derived frombotanical waxes, for example, sugar cane wax, rice bran and other cerealwaxes and bees wax. The most important of these are the long chain(C24-C36) primary alcohols, octacosanol, triacontanol and hexacosanol.

Policosanols, as noted above, are known to have a number of beneficialeffects on blood lipid health. These beneficial effects include loweringblood cholesterol levels, reducing Low Density Lipoproteins (LDL),increasing High Density Lipoproteins (HDL) and reducing bloodtriglycerides.

Some difficulties have been experienced in using policosanols to improveblood lipid health. For example, these fatty alcohols are poorly solublein lipid carriers and completely insoluble in aqueous carriers. Thisgreatly reduces their availability in the digestive tract. Normaldigestion of fats and oils in the mammalian diet is achieved byemulsification with bile salts and phospholipids followed by directadsorption of the resulting chylomicrons through the gut wall. Typicalchylomicron sizes are 0.5 microns to 2 microns.

Modern emulsification technology (nanotechnology) now makes it possibleto produce dispersed particle sizes in liquid carriers into the 1 micronsize. As noted above, many different physical emulsification techniquesare available.

In accordance with a non-limiting example of the present invention, oneor more of these technologies is used to prepare a dietary supplementcomposition in which the policosanol particle sizes are substantiallyless than 10 micron range within an acceptable oil carrier(Nanocosanol™). The composition may include the use of food-gradeemulsifiers, for example, polysorbates, lecithin, hydrolyzed lecithin,mono- and di-glycerides, and acylated mono- and di-glycerides. Thepresence of the emulsifiers inhibits the tendency of the particles toadhere under electrostatic attractive forces. Such a composition has theadvantage of increased digestibility and stability on storage.

In one aspect, the composition includes the selection of an oil carrierwith beneficial blood lipid properties. Such fats and oils may includepolyunsaturated fatty acids, omega-3 fatty acids, squalene,phytosterols, tocopherols and tocotrienols. Typical fats and oilsinclude, for example, fish oils, shark liver oil, cranberry seed oil,amaranth seed oil, sunflower seed oil, linseed oil, chia oil and eveningprimrose seed oil.

In another aspect, the composition optimizes the balanced intake of bothpolicosanols and the beneficial lipid carrier. By suitable selection ofthe ratio of the carrier oil to the policosanols, it is possible toproduce the composition such that preferred intakes of both policosanolsand the beneficial lipid can be conveniently administered in acceptableunit and daily doses.

Such a composition as (Nanocosanol™) can be used to promote and supportblood lipid health. Daily intake of such composition, in the preferreddose range, will provide the subject with the desired daily intakes ofpolicosanols and lipid carrier, resulting in improved blood lipidprofiles. This can include, for example, lower cholesterol, lowertriglycerides, lower Low Density Lipoprotein (LDL) and higher HighDensity Lipoprotein (HDL).

In accordance with one aspect of the present invention, a dietarysupplement composition is disclosed (Nanocosanol™) in which poorlysoluble policosanols are dispersed in food-grade oils or fats, in whichthe policosanol particle sizes in the composition are substantially lessthan 10 microns and preferably in the range of from about 0.2 microns toabout 5.0 microns.

In accordance with another aspect of the present invention, the body'sabsorption and utilization of the policosanols from the composition issubstantially enhanced as compared with the absorption and utilizationof policosanols administered in solid or tablet form. The policosanoldispersion of the composition is stable on storage and does not separatefrom the lipid carrier.

The disclosed lipid carrier used in the composition may be selected froma group of oils and or fats that are known to have beneficial effects onblood lipid health. Such beneficial lipids, for example, may contain oneor more of polyunsaturated fatty acids, phytosterols, omega-3 fattyacids, squalene, tocopherols and tocotrienols.

The concentration of policosanols of the composition optimizes the dailyintake of both policosanols and the beneficial lipid carrier. Thepreferred daily intake of policosanols can be about 20-30 mg per day foran adult. The preferred daily intake for beneficial lipids, however, isoften as high as from about 500 mg to 5,000 mg per day for an adult. Theweight of policosanols in the disclosed composition is from about 0.3percent by weight of beneficial lipid to about 5.0 percent by weight ofbeneficial lipid. Such a disclosed composition allows the ratio ofbeneficial lipid to policosanols to range from about 333:1 to about20:1. This ratio ensures that a policosanol intake of about 25 mg perday is always in combination with from about 500 mg per day to about5,000 mg per day of the beneficial lipid. The disclosed compositionallows delivery of a preferred daily dose of both policosanols andbeneficial lipid in a single formulation.

It will be understood by those in the art that liquid dietary supplementdaily doses of from about 500 mg to about 5,000 mg can be convenientlydelivered in capsules from about 500 mg to about 1,000 mg. For example,a three percent dispersion of policosanols in a beneficial lipid canconveniently supply 24 mg of policosanols per day together with 800 mgof beneficial lipid, when taken as two 400 mg capsules daily.

It will be understood by those in the art that such a composition, incapsule or liquid form, may be conveniently supplemented with otherbiologically active extracts and compounds, including, for example,vitamins, minerals, antioxidants, carotenoids, tocopherols,tocotrienols, phytosterols, fatty alcohols, polysaccharides andbioflavonoids.

The disclosed dietary supplement composition (Nanocosanol™) is a novel,improved, more efficient vehicle for the administration of policosanolsin support of blood lipid health. It is effective in lowering the bloodserum cholesterol level of both normal and hypercholesterolemicsubjects.

The following examples are illustrative of the present invention, andare not to be construed as limiting thereof.

Example 1

Supercritical CO₂ Extracts of Cranberry (Vaccinium macrocarpon) Seed,Amaranth (Amaranthus hypochondriacus) Seed and Rice (Oryza sativa) branwax were individually manufactured in a commercial 150 liter extractionunit. Within a heated vessel, the policosanol containing rice bran waxextract was dissolved into a mixture of cranberry and amaranth seed oilyextracts at 65° C. After cooling to ambient temperature, soybeanlecithin was combined. This resultant formulation was processed in ahigh pressure homogenization unit to obtain a stable dispersion of ricebran wax. The homogenizer is designed to produce high rates of shear andcavitation. Using light microscopy, average particle size wasdetermined. Composition of the dispersion was as follows:

Policosanols: 1.45%, average particle size 0.3-2.6 μm. alpha-Linolenicacid: 13.2% Squalene: 3% Tocopherols: 499 μg/g Tocotrienols: 709 μg/gPhytosterols: 4.4 mg/g

Example 2

The Nanocosanol formulation from Example 1 was encapsulated in standardgelatin softgels by a third party manufacturer. Softgels were 690 mgnominal fill weight and each contained 10 mg policosanol, 21 mgsqualene, 91 mg n-3 fatty acids (alphalinolenic), 3.0 mg phytosterols,489 μg tocotrienols and 344 μg tocopherols.

Example 3

Nanocosanol™ softgels, manufactured according to Example 2 wereadministered to 11 subjects over an approximately 3 month period. Thestudy was a non-placebo controlled open label trial and used volunteerswith normal and modestly elevated levels of serum cholesterol. Startingpoint individual cholesterol levels ranged from about 140 to about 258.Dosage was 2×600 mg capsules per day providing 20 mg per day ofpolicosanols together with 1200 mg per day of a 50:50 mixture ofCranberry and Amaranth Seed oils. In addition to the Policosonols, theNanocosanol™ formulation provided tocopherols, tocotrienols, omega-s andomega-3 fatty acids, polyunsaturated fatty acids and squalene.

Subject blood samples were taken by an independent clinic at 0 (Base),30, 60 and 90 days. The blood samples were subjected to Blood Lipid byan authorized independent laboratory.

Variables measured were Triglycerides, Cholesterol, LDL Cholesterol andHDL Cholesterol.

All data were expressed as a difference (change) from the Base level forthat subject and that variable. One subject did not complete a bloodsample at 90 days so the total number of observations was 32 (11, 11,10). Analyses were based the combined data over all three periods. Themean changes for the Blood Lipid variables were:

Triglycerides −4.72% p = 0.175 LDL Chol. −10.06% p = 0.125 HDL Chol.+1.85% p = 0.175 OTHER Chol. −5.23% p = 0.125 Chol. −5.96% p = 0.050LDL/HDL −11.73% p = 0.050 Chol/HDL −7.43% p = 0.050

The Cholesterol reduction of 5.96% was significant at the 5% level ofprobability using the One-Sided t-test with 31 DF, as were the LDL/HDLratio and the Chol/HDL ratio. The other Blood Lipid decreases are notsignificant at the 5% Level but have only a 1 in 6 to about 1 in 8chance of occurring by chance.

The mean changes for the blood liver variables were:

AST −7.06% p = 0.050 ALT −13.78% p = 0.050 AST/ALT +7.39% p = 0.050

AST and ALT in the combined data were both significantly reduced at the5% level of probability using the Two-Sided t-test with 31 DF. TheAST/ALT ratio was significantly increased at the 5% level, as a resultof ALT showing the greater reduction.

Analysis of Covariance was used to estimate the linear regression ofvariable change on variable Base level. The analyses tested thewithin-period regressions, differences between them, the pooled withinperiod regression, the regression-adjusted means and the overallregression. Both the pooled within period regression coefficient and theoverall regression coefficient for most variables were negative, highlysignificant at the 1% level (1 and 30 DF) and virtually identical.

Within period analyses for the Blood Lipid variables showed at least oneperiod gave a significant regression of change on Base level at the 5%level with 1 and 9 DF. For all such variables except HDL the regressioncoefficients were negative in each period. For HDL the regressioncoefficients were positive in all three periods.

Within period analyses of the Blood Liver Variables showed consistentnegative regression coefficients for AST and ALT although none werestatistically significant.

All variables showed no evidence of within period differences betweenthe regression coefficients or between the regression adjusted means.This would be expected given that the Base levels were identical foreach period.

Both the pooled within period regression coefficient and the overallregression coefficient for most variables were negative, highlysignificant at the 1% level (1 and 30 DF) and virtually identical. Theexceptions were HDL and AST/ALT.

Using the estimated regression equation, an estimate of the variablereduction resulting from a “typical high-quartile” Base level wascalculated for each variable. These are shown as follows. No attempt wasmade to put Standard Errors on the estimates.

Triglyceride b = −0.2918 p < 0.010 Base = 200 Chng = −29.92 (−14.62%)LDL b = −0.8234 p < 0.010 Base = 150 Chng = −34.34 (−22.89%) HDL b =+0.0854 p = 0.175 OTHER Chol b = −0.2870 p < 0.010 Base = 35 Chng =−4.43 (−12.66%) Chol b = −0.7704 p < 0.010 Base = 225 Chng = −24.27(−10.78%) LDL/HDL b = −0.4534 p < 0.010 Base = 2.75 Chng = −0.52(−18.89%) Chol/HDL b = −0.3577 p < 0.010 Base = 5.00 Chng = −0.78(−15.52%) AST b = −0.5720 p < 0.010 Base = 25 Chng = −4.32 (−17.27%) ALTb = −0.3554 p < 0.010 Base = 25 Chng = −4.20 (−16.75%) AST/ALT b =−0.0661 N.S.

The treatment resulted in significant and near significant reductionsover base level for all Blood Lipid variables except HDL which showed asmall increase. This slight increase in HDL should be seen as being apositive result. Nanocosanol was clearly and demonstrably responsiblefor a significant improvement in blood lipid health. This is mostclearly established for Total Cholesterol and the critical LDL/HDL andChol/HDL ratios. It is also likely that in a larger sample size, thereductions in Triglycerides and LDL and the increase in HDL, bothdesirable treatment effects, could be confirmed as significant.

The treatment resulted in highly significant reductions over Base levelfor AST and ALT and an increase for the AST/ALT ratio. The reduction inblood aminotransferases is unexpected. These tests are designed todetect elevated values as an indicator of liver damage. However, it isnot clear whether a reduction in these enzyme levels is an indicator of“improved” liver health. This aspect of the study requires furtherspecific trial work.

The fact that significant results were obtained using all 32 data pointsbut not with the 11 data points in each period, is possibly due tonothing other than sample size. However, it does point out that thereductions in Blood Lipid values occur fairly quickly followingNanocosanol treatment, with on-going reductions proceeding very slowly,if at all.

The most important result is the demonstration that decreases in bothBlood Lipid and Blood Liver values are a function of the Base level.These results suggest that Nanocosanol will have very little effect onsubjects with low to normal blood values. However for those subjects inthe population with elevated values, Nanocosanol could have thepotential to bring about 15-20% reductions in a very short time.

The positive side effects mentioned effects included a reduction ingastrointestinal esophageal reflux disease (GERD) symptoms (reported by3 subjects) and reduction of irritable bowel syndrome symptoms wasreported by one volunteer. Seven (64%) of the volunteers reported anincrease in the number of bowl movements without a significant stoolsoftening. In some cases the number of bowl movements increased twofoldwithout any negative impacts. At each blood draw each volunteer wasasked to fill out a report about any negative or positive side effects.Over half of the trial participants reported positive health impactswhile zero negative side effects were reported.

Typically, the manifestation and improvements in irritable bowelsyndrome could include not only a reduction in the number of bowelmovements per day when those bowel movements are excessive, but also anincrease in weekly bowel movements when the weekly bowel movements areminimal, such as only two or three bowel movements per week. Althoughthe exact mechanism for the dietary or brain-gut response is notcompletely known, the results have been positive.

As to GERD, in some cases, it is typically caused by a failure of thecardia or minimal stomach acid. The method using the compositioneffectively counteracts such causes in some of the sampled subjects asnoted above.

Many modifications and other embodiments of the invention will come tothe mind of one skilled in the art having the benefit of the teachingspresented in the foregoing descriptions and the associated drawings.Therefore, it is understood that the invention is not to be limited tothe specific embodiments disclosed, and that modifications andembodiments are intended to be included within the scope of the appendedclaims.

1. A method for enhancing gastrointestinal motility in humans and othermammals, comprising administering a therapeutically effective amount ofa composition having one or more long chain (C24-C36) primary alcoholsas policosanols dispersed in one or more food-grade fats or oils,wherein the particle sizes of the alcohols are substantially less than10 microns.
 2. The method according to claim 1, wherein the compositionis administered in a therapeutically effective amount for reducinggastrointestinal esophageal reflux disease (GERD) symptoms.
 3. Themethod according to claim 1, wherein the composition is administered ina therapeutically effective amount for reducing irritable bowel syndromesymptoms.
 4. The method according to claim 1, wherein the particle sizesof the alcohols are substantially greater than 0.2 microns andsubstantially less than 5.0 microns.
 5. The method according to claim 1,wherein the alcohols are selected from natural sources comprising ricebran, beeswax, sugar cane, sorghum or wheat.
 6. The method according toclaim 1, wherein the food-grade fats or oils contain one of at least:(a) not less than twenty five percent (25%) by weight of polyunsaturatedfatty acids; (b) not less than ten percent (10%) by weight of omega-3fatty acids; (c) not less than two and one-half percent (2.5%) by weightof squalene; and (d) not less than eight fifty parts per million (850ppm) by weight of tocopherols and tocotrienols in total.
 7. The methodaccording to claim 1, wherein the food-grade fats or oils comprise atleast one of cranberry seed oil, amaranth seed oil, fish andmarine/algal oils, safflower oil, sunflower seed oil, soybean oil,canola oil, olive oil, linseed oil, flax oil, hemp oil, borage oil,evening primrose oil, chia oil and hibiscus oil.
 8. The method accordingto claim 1, wherein the policosanols comprise from about 0.1 percent byweight of the fats or oils to about 6.0 percent by weight of the fats oroils.
 9. The method according to claim 1, wherein the policosanolscomprise from about 0.5% by weight of the fats or oils to about 5.0% byweight of the fats or oils.
 10. The method according to claim 1, whereinthe policosanols comprise from about 1.0% by weight of the fats or oilsto about 5.0% by weight of the fats or oils.
 11. The method according toclaim 1, and further comprising biologically active extracts andcompounds, including vitamins, minerals, antioxidants, carotenoids,tocopherols, tocotrienols, phytosterols, polyphenols, polysaccharidesand bioflavonoids.
 12. The method according to claim 1, and furthercomprising a delivery vehicle as an emulsion, solution, dispersion,cream, tablet, capsules and powder.
 13. The method according to claim 1,and further comprising a delivery vehicle for carrying the compositioncomprising food, feed or beverage.